Current Diabetes Reports

, 11:364 | Cite as

Alternative Transplantation Sites for Pancreatic Islet Grafts

  • Elisa Cantarelli
  • Lorenzo Piemonti


The liver is the current site of choice for pancreatic islet transplantation, even though it is far from being an ideal site because of immunologic, anatomic, and physiologic factors leading to a significant early graft loss. A huge amount of alternative sites have been used for islet transplantation in experimental animal models to provide improved engraftment and long-term survival minimizing surgical complications. The pancreas, gastric submucosa, genitourinary tract, muscle, omentum, bone marrow, kidney capsule, peritoneum, anterior eye chamber, testis, and thymus have been explored. Site-specific differences exist in term of islet engraftment, but few alternative sites have potential clinical translation and generally the evidence of a post-transplant islet function better than that reached after intraportal infusion is still lacking. This review discusses site-specific benefits and drawbacks taking into account immunologic, metabolic, and technical aspects to identify the ideal microenvironment for islet function and survival.


Islet transplantation Alternative site Intravascular sites Extravascular sites Immunoprivileged sites Microenvironment Engraftment Early challenges Late challenges Pancreatic islet graft 



No potential conflicts of interest relevant to this article were reported.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Kemp CB et al. Effect of transplantation site on the results of pancreatic islet isografts in diabetic rats. Diabetologia. 1973;9(6):486–91.PubMedCrossRefGoogle Scholar
  2. 2.
    Najarian JS et al. Total or near total pancreatectomy and islet autotransplantation for treatment of chronic pancreatitis. Ann Surg. 1980;192(4):526–42.PubMedCrossRefGoogle Scholar
  3. 3.
    Sutherland DE et al. Transplantation of dispersed pancreatic islet tissue in humans: autografts and allografts. Diabetes. 1980;29 Suppl 1:31–44.PubMedGoogle Scholar
  4. 4.
    Scharp DW et al. Insulin independence after islet transplantation into type I diabetic patient. Diabetes. 1990;39(4):515–8.PubMedCrossRefGoogle Scholar
  5. 5.
    • Melzi R et al. Intrahepatic islet transplant in the mouse: functional and morphological characterization. Cell Transplant. 2008;17(12):1361–70. This study demonstrated that islet transplantation via the portal vein in the mouse model has similar features to human islet transplantation and should be used as a model to study not only engraftment but also mechanisms of immune suppression and tolerance.PubMedCrossRefGoogle Scholar
  6. 6.
    Toyofuku A et al. Natural killer T-cells participate in rejection of islet allografts in the liver of mice. Diabetes. 2006;55(1):34–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Yasunami Y et al. Valpha14 NK T cell-triggered IFN-gamma production by Gr-1 + CD11b + cells mediates early graft loss of syngeneic transplanted islets. J Exp Med. 2005;202(7):913–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Carlsson PO et al. Markedly decreased oxygen tension in transplanted rat pancreatic islets irrespective of the implantation site. Diabetes. 2001;50(3):489–95.PubMedCrossRefGoogle Scholar
  9. 9.
    Korsgren O et al. Optimising islet engraftment is critical for successful clinical islet transplantation. Diabetologia. 2008;51(2):227–32.PubMedCrossRefGoogle Scholar
  10. 10.
    •• Eriksson O et al. Positron emission tomography in clinical islet transplantation. Am J Transplant. 2009;9(12):2816–24. This study demonstrated that positron emission tomography combined with CT allows real-time quantitative and qualitative measurements of islet kinetics and distribution during the first hours after islet infusion in the portal vein.PubMedCrossRefGoogle Scholar
  11. 11.
    Barshes NR et al. Transaminitis after pancreatic islet transplantation. J Am Coll Surg. 2005;200(3):353–61.PubMedCrossRefGoogle Scholar
  12. 12.
    Rafael E et al. Changes in liver enzymes after clinical islet transplantation. Transplantation. 2003;76(9):1280–4.PubMedCrossRefGoogle Scholar
  13. 13.
    • Sakata N et al. MRI assessment of ischemic liver after intraportal islet transplantation. Transplantation. 2009;87(6):825–30. This paper showed that MRI is useful for the detection and quantification of ischemic, necrotic and apoptotic areas in ex vivo murine livers after islet transplantation.PubMedCrossRefGoogle Scholar
  14. 14.
    Venturini M et al. Technique, complications, and therapeutic efficacy of percutaneous transplantation of human pancreatic islet cells in type 1 diabetes: the role of US. Radiology. 2005;234(2):617–24.PubMedCrossRefGoogle Scholar
  15. 15.
    Ferguson J, Scothorne RJ, Johnston ID. Proceedings: the survival of transplanted isolated pancreatic islets in the omentum and testis. Br J Surg. 1973;60(11):907.PubMedGoogle Scholar
  16. 16.
    Kim HI et al. Comparison of four pancreatic islet implantation sites. J Korean Med Sci. 2010;25(2):203–10.PubMedCrossRefGoogle Scholar
  17. 17.
    Pileggi A et al. Impact of pancreatic cold preservation on rat islet recovery and function. Transplantation. 2009;87(10):1442–50.PubMedCrossRefGoogle Scholar
  18. 18.
    Paraskevas S et al. Activation and expression of ERK, JNK, and p38 MAP-kinases in isolated islets of Langerhans: implications for cultured islet survival. FEBS Lett. 1999;455(3):203–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Abdelli S et al. Intracellular stress signaling pathways activated during human islet preparation and following acute cytokine exposure. Diabetes. 2004;53(11):2815–23.PubMedCrossRefGoogle Scholar
  20. 20.
    Sklavos MM et al. Redox modulation protects islets from transplant-related injury. Diabetes. 2010;59(7):1731–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Barshes NR, Wyllie S, Goss JA. Inflammation-mediated dysfunction and apoptosis in pancreatic islet transplantation: implications for intrahepatic grafts. J Leukoc Biol. 2005;77(5):587–97.PubMedCrossRefGoogle Scholar
  22. 22.
    Bennet W et al. Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation? Diabetes. 1999;48(10):1907–14.PubMedCrossRefGoogle Scholar
  23. 23.
    Ozmen L et al. Inhibition of thrombin abrogates the instant blood-mediated inflammatory reaction triggered by isolated human islets: possible application of the thrombin inhibitor melagatran in clinical islet transplantation. Diabetes. 2002;51(6):1779–84.PubMedCrossRefGoogle Scholar
  24. 24.
    •• Moberg L et al. Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation. Lancet. 2002;360(9350):2039–45.PubMedCrossRefGoogle Scholar
  25. 25.
    Johansson H et al. Tissue factor produced by the endocrine cells of the islets of Langerhans is associated with a negative outcome of clinical islet transplantation. Diabetes. 2005;54(6):1755–62.PubMedCrossRefGoogle Scholar
  26. 26.
    Yin D et al. Liver ischemia contributes to early islet failure following intraportal transplantation: benefits of liver ischemic-preconditioning. Am J Transplant. 2006;6(1):60–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Bottino R et al. Transplantation of allogeneic islets of Langerhans in the rat liver: effects of macrophage depletion on graft survival and microenvironment activation. Diabetes. 1998;47(3):316–23.PubMedCrossRefGoogle Scholar
  28. 28.
    Moberg L, Korsgren O, Nilsson B. Neutrophilic granulocytes are the predominant cell type infiltrating pancreatic islets in contact with ABO-compatible blood. Clin Exp Immunol. 2005;142(1):125–31.PubMedCrossRefGoogle Scholar
  29. 29.
    Bertuzzi F et al. Tissue factor and CCL2/monocyte chemoattractant protein-1 released by human islets affect islet engraftment in type 1 diabetic recipients. J Clin Endocrinol Metab. 2004;89(11):5724–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Piemonti L et al. Human pancreatic islets produce and secrete MCP-1/CCL2: relevance in human islet transplantation. Diabetes. 2002;51(1):55–65.PubMedCrossRefGoogle Scholar
  31. 31.
    Johansson U et al. Inflammatory mediators expressed in human islets of Langerhans: implications for islet transplantation. Biochem Biophys Res Commun. 2003;308(3):474–9.PubMedCrossRefGoogle Scholar
  32. 32.
    • Matsuoka N et al. High-mobility group box 1 is involved in the initial events of early loss of transplanted islets in mice. J Clin Invest. 2010;120(3):735–43. The present study investigated in the mouse model the mechanisms involved in the early loss of transplanted islets focusing the attention on HMGB1 as a mediator of cell damage. These results demonstrated that HMGB1 is released from intraliver-infused islets and stimulates the production of inflammatory cytokines, which in turn accelerates graft injury.PubMedCrossRefGoogle Scholar
  33. 33.
    Tiedge M et al. Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetes. 1997;46(11):1733–42.PubMedCrossRefGoogle Scholar
  34. 34.
    Robertson RP, Harmon JS. Pancreatic islet beta-cell and oxidative stress: the importance of glutathione peroxidase. FEBS Lett. 2007;581(19):3743–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Scapini P et al. The neutrophil as a cellular source of chemokines. Immunol Rev. 2000;177:195–203.PubMedCrossRefGoogle Scholar
  36. 36.
    Ballian N, Brunicardi FC. Islet vasculature as a regulator of endocrine pancreas function. World J Surg. 2007;31(4):705–14.PubMedCrossRefGoogle Scholar
  37. 37.
    Jansson L, Carlsson PO. Graft vascular function after transplantation of pancreatic islets. Diabetologia. 2002;45(6):749–63.PubMedCrossRefGoogle Scholar
  38. 38.
    Brissova M et al. Intraislet endothelial cells contribute to revascularization of transplanted pancreatic islets. Diabetes. 2004;53(5):1318–25.PubMedCrossRefGoogle Scholar
  39. 39.
    Carlsson PO, Palm F, Mattsson G. Low revascularization of experimentally transplanted human pancreatic islets. J Clin Endocrinol Metab. 2002;87(12):5418–23.PubMedCrossRefGoogle Scholar
  40. 40.
    Lau J et al. Implantation site-dependent dysfunction of transplanted pancreatic islets. Diabetes. 2007;56(6):1544–50.PubMedCrossRefGoogle Scholar
  41. 41.
    Nyqvist D et al. Donor islet endothelial cells participate in formation of functional vessels within pancreatic islet grafts. Diabetes. 2005;54(8):2287–93.PubMedCrossRefGoogle Scholar
  42. 42.
    Vajkoczy P et al. Histogenesis and ultrastructure of pancreatic islet graft microvasculature. Evidence for graft revascularization by endothelial cells of host origin. Am J Pathol. 1995;146(6):1397–405.PubMedGoogle Scholar
  43. 43.
    Desai NM et al. Elevated portal vein drug levels of sirolimus and tacrolimus in islet transplant recipients: local immunosuppression or islet toxicity? Transplantation. 2003;76(11):1623–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Shapiro AM et al. The portal immunosuppressive storm: relevance to islet transplantation? Ther Drug Monit. 2005;27(1):35–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Cantaluppi V et al. Antiangiogenic and immunomodulatory effects of rapamycin on islet endothelium: relevance for islet transplantation. Am J Transplant. 2006;6(11):2601–11.PubMedCrossRefGoogle Scholar
  46. 46.
    Zhang N et al. Sirolimus is associated with reduced islet engraftment and impaired beta-cell function. Diabetes. 2006;55(9):2429–36.PubMedCrossRefGoogle Scholar
  47. 47.
    Zahr E et al. Rapamycin impairs in vivo proliferation of islet beta-cells. Transplantation. 2007;84(12):1576–83.PubMedCrossRefGoogle Scholar
  48. 48.
    Nir T, Melton DA, Dor Y. Recovery from diabetes in mice by beta cell regeneration. J Clin Invest. 2007;117(9):2553–61.PubMedCrossRefGoogle Scholar
  49. 49.
    Leitao CB et al. Lipotoxicity and decreased islet graft survival. Diabetes Care. 2010;33(3):658–60.PubMedCrossRefGoogle Scholar
  50. 50.
    Dombrowski F, Mathieu C, Evert M. Hepatocellular neoplasms induced by low-number pancreatic islet transplants in autoimmune diabetic BB/Pfd rats. Cancer Res. 2006;66(3):1833–43.PubMedCrossRefGoogle Scholar
  51. 51.
    Markmann JF et al. Magnetic resonance-defined periportal steatosis following intraportal islet transplantation: a functional footprint of islet graft survival? Diabetes. 2003;52(7):1591–4.PubMedCrossRefGoogle Scholar
  52. 52.
    Bhargava R et al. Prevalence of hepatic steatosis after islet transplantation and its relation to graft function. Diabetes. 2004;53(5):1311–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Stagner JI, Rilo HL, White KK. The pancreas as an islet transplantation site. Confirmation in a syngeneic rodent and canine autotransplant model. JOP. 2007;8(5):628–36.PubMedGoogle Scholar
  54. 54.
    Carlsson PO et al. Measurements of oxygen tension in native and transplanted rat pancreatic islets. Diabetes. 1998;47(7):1027–32.PubMedCrossRefGoogle Scholar
  55. 55.
    Caiazzo R et al. Evaluation of alternative sites for islet transplantation in the minipig: interest and limits of the gastric submucosa. Transplant Proc. 2007;39(8):2620–3.PubMedCrossRefGoogle Scholar
  56. 56.
    Wszola M et al. TransEndoscopic Gastric SubMucosa Islet Transplantation (eGSM-ITx) in pigs with streptozotocine induced diabetes - technical aspects of the procedure - preliminary report. Ann Transplant. 2009;14(2):45–50.PubMedGoogle Scholar
  57. 57.
    Echeverri GJ et al. Endoscopic gastric submucosal transplantation of islets (ENDO-STI): technique and initial results in diabetic pigs. Am J Transplant. 2009;9(11):2485–96.PubMedCrossRefGoogle Scholar
  58. 58.
    Burgos FJ et al. Pancreas islet transplantation in the genitourinary tract associated with renal transplantation: an experimental study. Transplant Proc. 2006;38(8):2585–7.PubMedCrossRefGoogle Scholar
  59. 59.
    Stegall MD et al. Evidence of recurrent autoimmunity in human allogeneic islet transplantation. Transplantation. 1996;61(8):1272–4.PubMedCrossRefGoogle Scholar
  60. 60.
    Weber CJ et al. Tissue culture preservation and intramuscular transplantation of pancreatic islets. Surgery. 1978;84(1):166–74.PubMedGoogle Scholar
  61. 61.
    Rafael E et al. Intramuscular autotransplantation of pancreatic islets in a 7-year-old child: a 2-year follow-up. Am J Transplant. 2008;8(2):458–62.PubMedCrossRefGoogle Scholar
  62. 62.
    Svensson J et al. High Vascular Density and Oxygenation of Pancreatic Islets Transplanted in Clusters into Striated Muscle. Cell Transplant. 2010 Nov 5. [Epub ahead of print]Google Scholar
  63. 63.
    Christoffersson G et al. Clinical and experimental pancreatic islet transplantation to striated muscle: establishment of a vascular system similar to that in native islets. Diabetes. 2010;59(10):2569–78.PubMedCrossRefGoogle Scholar
  64. 64.
    Lund T et al. Sustained reversal of diabetes following islet transplantation to striated musculature in the rat. J Surg Res. 2010;160(1):145–54.PubMedCrossRefGoogle Scholar
  65. 65.
    Fritschy WM et al. The efficacy of intraperitoneal pancreatic islet isografts in the reversal of diabetes in rats. Transplantation. 1991;52(5):777–83.PubMedCrossRefGoogle Scholar
  66. 66.
    Lorenz D et al. Transplantation of isologous islets of Langerhans in diabetic rats. Acta Diabetol Lat. 1975;12(1):30–40.PubMedCrossRefGoogle Scholar
  67. 67.
    Kobayashi T et al. Indefinite islet protection from autoimmune destruction in nonobese diabetic mice by agarose microencapsulation without immunosuppression. Transplantation. 2003;75(5):619–25.PubMedCrossRefGoogle Scholar
  68. 68.
    Wahoff DC et al. Intraperitoneal transplantation of microencapsulated canine islet allografts with short-term, low-dose cyclosporine for treatment of pancreatectomy-induced diabetes in dogs. Transplant Proc. 1994;26(2):804.PubMedGoogle Scholar
  69. 69.
    Qi M et al. A recommended laparoscopic procedure for implantation of microcapsules in the peritoneal cavity of non-human primates. J Surg Res. 2011;168(1):e117–23.PubMedCrossRefGoogle Scholar
  70. 70.
    Elliott RB et al. Intraperitoneal alginate-encapsulated neonatal porcine islets in a placebo-controlled study with 16 diabetic cynomolgus primates. Transplant Proc. 2005;37(8):3505–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Calafiore R et al. Microencapsulated pancreatic islet allografts into nonimmunosuppressed patients with type 1 diabetes: first two cases. Diabetes Care. 2006;29(1):137–8.PubMedCrossRefGoogle Scholar
  72. 72.
    al-Abdullah IH et al. Site for unpurified islet transplantation is an important parameter for determination of the outcome of graft survival and function. Cell Transplant. 1995;4(3):297–305.PubMedCrossRefGoogle Scholar
  73. 73.
    Kin T, Korbutt GS, Rajotte RV. Survival and metabolic function of syngeneic rat islet grafts transplanted in the omental pouch. Am J Transplant. 2003;3(3):281–5.PubMedCrossRefGoogle Scholar
  74. 74.
    Ao Z et al. Survival and function of purified islets in the omental pouch site of outbred dogs. Transplantation. 1993;56(3):524–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Gustavson SM et al. Islet auto-transplantation into an omental or splenic site results in a normal beta cell but abnormal alpha cell response to mild non-insulin-induced hypoglycemia. Am J Transplant. 2005;5(10):2368–77.PubMedCrossRefGoogle Scholar
  76. 76.
    Berman DM et al. Long-term survival of nonhuman primate islets implanted in an omental pouch on a biodegradable scaffold. Am J Transplant. 2009;9(1):91–104.PubMedCrossRefGoogle Scholar
  77. 77.
    Litbarg NO et al. Activated omentum becomes rich in factors that promote healing and tissue regeneration. Cell Tissue Res. 2007;328(3):487–97.PubMedCrossRefGoogle Scholar
  78. 78.
    Ferguson J, Scothorne RJ. Extended survival of pancreatic islet allografts in the testis of guinea-pigs. J Anat. 1977;124(Pt 1):1–8.PubMedGoogle Scholar
  79. 79.
    •• Cantarelli E et al. Bone marrow as an alternative site for islet transplantation. Blood. 2009;114(20):4566–74. This paper demonstrated both the efficacy and safety of BM as an alternative site for islet implantation in the mouse model.PubMedCrossRefGoogle Scholar
  80. 80.
    Salazar-Banuelos A et al. Pancreatic islet transplantation into the bone marrow of the rat. Am J Surg. 2008;195(5):674–8. discussion 678.PubMedCrossRefGoogle Scholar
  81. 81.
    Frassoni F et al. Direct intrabone transplant of unrelated cord-blood cells in acute leukaemia: a phase I/II study. Lancet Oncol. 2008;9(9):831–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Szot GL, Koudria P, Bluestone JA. Transplantation of pancreatic islets into the kidney capsule of diabetic mice. J Vis Exp. 2007;9:404.PubMedGoogle Scholar
  83. 83.
    Carlsson PO et al. Chronically decreased oxygen tension in rat pancreatic islets transplanted under the kidney capsule. Transplantation. 2000;69(5):761–6.PubMedCrossRefGoogle Scholar
  84. 84.
    van Suylichem PT et al. Rat islet isograft function. Effect of graft volume and transplantation site. Transplantation. 1994;57(7):1010–7.PubMedGoogle Scholar
  85. 85.
    Song HJ et al. Prolongation of islet graft survival using concomitant transplantation of islets and vascular endothelial cells in diabetic rats. Transplant Proc. 2010;42(7):2662–5.PubMedCrossRefGoogle Scholar
  86. 86.
    Rackham CL et al. Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice. Diabetologia. 2011;54(5):1127–35.PubMedCrossRefGoogle Scholar
  87. 87.
    Sordi V et al. Mesenchymal cells appearing in pancreatic tissue culture are bone marrow-derived stem cells with the capacity to improve transplanted islet function. Stem Cells. 2010;28(1):140–51.PubMedGoogle Scholar
  88. 88.
    Sakata N et al. Bone marrow cell cotransplantation with islets improves their vascularization and function. Transplantation. 2010;89(6):686–93.PubMedCrossRefGoogle Scholar
  89. 89.
    Melzi R et al. Co-graft of allogeneic immune regulatory neural stem cells (NPC) and pancreatic islets mediates tolerance, while inducing NPC-derived tumors in mice. PLoS One. 2010;5(4):e10357.PubMedCrossRefGoogle Scholar
  90. 90.
    Dufour JM et al. Comparison of successful and unsuccessful islet/Sertoli cell cotransplant grafts in streptozotocin-induced diabetic mice. Cell Transplant. 2008;16(10):1029–38.PubMedCrossRefGoogle Scholar
  91. 91.
    Adeghate E, Donath T. Morphological findings in long-term pancreatic tissue transplants in the anterior eye chamber of rats. Pancreas. 1990;5(3):298–305.PubMedCrossRefGoogle Scholar
  92. 92.
    • Speier S et al. Noninvasive in vivo imaging of pancreatic islet cell biology. Nat Med. 2008;14(5):574–8. This paper validated a noninvasive in vivo fluorescence imaging method to study islet revascularization and composition and β-cell function and death at cellular resolution.PubMedCrossRefGoogle Scholar
  93. 93.
    Perez VL et al. The anterior chamber of the eye as a clinical transplantation site for the treatment of diabetes: a study in a baboon model of diabetes. Diabetologia. 2011;54(5):1121–6.PubMedCrossRefGoogle Scholar
  94. 94.
    •• Bellin MD et al. Similar islet function in islet allotransplant and autotransplant recipients, despite lower islet mass in autotransplants. Transplantation. 2011;91(3):367–72. This study compared islet function between allo- and autoislet transplant recipients at a similar time post-infusion and showed a better preservation of islet mass in the autograft setting due to the lack of autoimmunity, alloimmunity, and immunosuppressive drug toxicity.PubMedCrossRefGoogle Scholar
  95. 95.
    • Vendrame F et al. Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells. Diabetes. 2010;59(4):947–57. This study demonstrated that recurrent islet autoimmunity, measured both as autoantibodies and autoantigen-specific CD4 T cells, explained the hyperglycemia and loss of insulin secretion observed in three immunosuppressed simultaneous pancreas-kidney transplant recipients in the absence of rejection.PubMedCrossRefGoogle Scholar
  96. 96.
    Bosi E et al. Autoantibody response to islet transplantation in type 1 diabetes. Diabetes. 2001;50(11):2464–71.PubMedCrossRefGoogle Scholar
  97. 97.
    • Roelen DL et al. Relevance of cytotoxic alloreactivity under different immunosuppressive regimens in clinical islet cell transplantation. Clin Exp Immunol. 2009;156(1):141–8. This observational study analyzed the influence of different immunosuppression therapies on autoreactive and alloreactive T-cell patterns and transplant outcome demonstrating that graft function correlates negatively with pretransplant cellular autoreactivity and is associated with the applied immunosuppressive regimen.PubMedCrossRefGoogle Scholar
  98. 98.
    Jaeger C et al. Islet autoantibodies as potential markers for disease recurrence in clinical islet transplantation. Exp Clin Endocrinol Diabetes. 2000;108(5):328–33.PubMedCrossRefGoogle Scholar
  99. 99.
    Braghi S et al. Modulation of humoral islet autoimmunity by pancreas allotransplantation influences allograft outcome in patients with type 1 diabetes. Diabetes. 2000;49(2):218–24.PubMedCrossRefGoogle Scholar
  100. 100.
    Roep BO et al. Auto- and alloimmune reactivity to human islet allografts transplanted into type 1 diabetic patients. Diabetes. 1999;48(3):484–90.PubMedCrossRefGoogle Scholar
  101. 101.
    Huurman VA et al. Cellular islet autoimmunity associates with clinical outcome of islet cell transplantation. PLoS One. 2008;3(6):e2435.PubMedCrossRefGoogle Scholar
  102. 102.
    Palmer JP et al. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21–22 October 2001. Diabetes. 2004;53(1):250–64.PubMedCrossRefGoogle Scholar
  103. 103.
    Pinkse GG et al. Autoreactive CD8 T cells associated with beta cell destruction in type 1 diabetes. Proc Natl Acad Sci U S A. 2005;102(51):18425–30.PubMedCrossRefGoogle Scholar
  104. 104.
    Griffith TS et al. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science. 1995;270(5239):1189–92.PubMedCrossRefGoogle Scholar
  105. 105.
    Bellgrau D et al. A role for CD95 ligand in preventing graft rejection. Nature. 1995;377(6550):630–2.PubMedCrossRefGoogle Scholar
  106. 106.
    Chen JJ, Sun Y, Nabel GJ. Regulation of the proinflammatory effects of Fas ligand (CD95L). Science. 1998;282(5394):1714–7.PubMedCrossRefGoogle Scholar
  107. 107.
    Wilbanks GA, Mammolenti M, Streilein JW. Studies on the induction of anterior chamber-associated immune deviation (ACAID). III. Induction of ACAID depends upon intraocular transforming growth factor-beta. Eur J Immunol. 1992;22(1):165–73.PubMedCrossRefGoogle Scholar
  108. 108.
    Margolis RN, Holup JJ, Selawry HP. Effects of intratesticular islet transplantation on hepatic glycogen metabolism in the rat. Diabetes Res Clin Pract. 1986;2(5):291–9.PubMedCrossRefGoogle Scholar
  109. 109.
    Dai Z et al. Impaired recall of CD8 memory T cells in immunologically privileged tissue. J Immunol. 2005;174(3):1165–70.PubMedGoogle Scholar
  110. 110.
    Ar'Rajab A et al. Immune privilege of the testis for islet xenotransplantation (rat to mouse). Cell Transplant. 1994;3(6):493–8.PubMedGoogle Scholar
  111. 111.
    Nasr IW et al. Testicular immune privilege promotes transplantation tolerance by altering the balance between memory and regulatory T cells. J Immunol. 2005;174(10):6161–8.PubMedGoogle Scholar
  112. 112.
    Gores PF et al. Long-term survival of intratesticular porcine islets in nonimmunosuppressed beagles. Transplantation. 2003;75(5):613–8.PubMedCrossRefGoogle Scholar
  113. 113.
    Valdes-Gonzalez RA et al. Xenotransplantation of porcine neonatal islets of Langerhans and Sertoli cells: a 4-year study. Eur J Endocrinol. 2005;153(3):419–27.PubMedCrossRefGoogle Scholar
  114. 114.
    Posselt AM et al. Induction of donor-specific unresponsiveness by intrathymic islet transplantation. Science. 1990;249(4974):1293–5.PubMedCrossRefGoogle Scholar
  115. 115.
    Rayat GR et al. Survival and function of syngeneic rat islet grafts placed within the thymus versus under the kidney capsule. Cell Transplant. 1997;6(6):597–602.PubMedCrossRefGoogle Scholar
  116. 116.
    Watt PC et al. Successful engraftment of autologous and allogeneic islets into the porcine thymus. J Surg Res. 1994;56(4):367–71.PubMedCrossRefGoogle Scholar
  117. 117.
    Ludwig B et al. A novel device for islet transplantation providing immune protection and oxygen supply. Horm Metab Res. 2010;42(13):918–22.PubMedCrossRefGoogle Scholar
  118. 118.
    Barnett BP et al. Fluorocapsules for improved function, immunoprotection, and visualization of cellular therapeutics with MR, US, and CT imaging. Radiology. 2011;258(1):182–91.PubMedCrossRefGoogle Scholar
  119. 119.
    Stiegler P et al. Creation of a prevascularized site for cell transplantation in rats. Xenotransplantation. 2010;17(5):379–90.PubMedCrossRefGoogle Scholar
  120. 120.
    Song C et al. Polyglycolic Acid-islet grafts improve blood glucose and insulin concentrations in rats with induced diabetes. Transplant Proc. 2009;41(5):1789–93.PubMedCrossRefGoogle Scholar
  121. 121.
    Kin T et al. The use of an approved biodegradable polymer scaffold as a solid support system for improvement of islet engraftment. Artif Organs. 2008;32(12):990–3.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.San Raffaele Diabetes Research Institute (HSR-DRI)San Raffaele Scientific InstituteMilanItaly
  2. 2.Beta Cell Biology Unit, Diabetes Research InstituteSan Raffaele Scientific InstituteMilanItaly

Personalised recommendations